We seek to capitalize on a substantial body of work has characterized the immune responses of HIV+ individuals with very slow disease progression (LTNP), and HIV- individuals who do not seroconvert despite repeated HIV exposure (ESN). A fraction of people in these groups produce natural anti-CCR5 antibodies that are associated with their disease-free status (in longitudinal studies loss of these antibodies results in disease progression). These antibodies are unique in that they bind a rare CCR5 epitope, induce a long term downregulation of CCR5 on the surface of cells, and can inhibit transcytosis of HIV across mucosal membranes. Experimentally raised polyclonal chicken antibodies to this epitope are even more potent than their human-derived counterparts with respect to these biological activities, and represent an opportunity to develop a unique product offering in the HIV/AIDS arena. We will use our proprietary technology to raise a panel of chicken monoclonal antibodies to this CCR5 epitope and humanize the most active members of this panel for further development. PUBLIC HEALTH RELEVANCE: An estimated 33.4 million people worldwide are now living with HIV, and 2.7 million are newly infected every year, with a higher prevalence among women, as women are biologically more vulnerable to HIV than men. Anti-viral drugs have proven effective in allowing HIV+ individuals to live longer disease-free lives. However, this success has done little to reduce the spread of HIV/AIDS worldwide, since it does not address HIV transmission between individuals. In principle, vaccines can solve this problem, although many years of intense effort have not yielded a product. The difficulty is to some extent due to the ability of HIV, more so than other viruses, to rapidly evolve and therefore evade a vaccine-centric immune response that is restricted by the physical structure of the vaccine itself. Furthermore, it is well known that HIV+ individuals produce antibodies to viral proteins, but generally these antibodies do not slow the progression of disease. For these reasons, a new strategy has emerged: to identify blocking antibodies against the HIV receptors or co-receptors, such as CCR5, rather than the virus itself. The receptors/co-receptors are native human proteins that HIV requires, but does not genetically control. However, since receptors are self proteins, it is unlikely that a vaccine approach will reliably generate a vigorous response in humans. The alternative is to develop potent antibodies independently in other species, and use humanized versions of them in the modality of passive immunotherapy. Antibodies that block HIV infection could potentially be used therapeutically in HIV+ individuals to reduce viral load and disease progression, and could also be used prophylactic ally to reduce transmission between individuals if present in the appropriate mucosal tissues. An innovative approach using a humanized chicken monoclonal antibody to a cryptic epitope on the HIV co- receptor CCR5 is anticipated to yield a candidate that is superior to other CCR5 antibodies in preclinical or clinicl development.